KR102392668B1 - Sustained Release Formulation Comprising Limaprost - Google Patents

Abstract

The present invention includes at least one selected from the group consisting of limaprost and limaprost alphadex as an active ingredient, ethyl cellulose as a sustained-release agent, hydroxypropyl betadex as a first stabilizer, and glyceryl behenate as a second stabilizer It provides a sustained-release formulation. The sustained-release formulation containing limaprost according to the present invention can maintain the drug concentration of limaprost appropriately even with twice a day dosing regimen, thereby exhibiting a continuous therapeutic effect and improving the stability of limaprost.

Description

Limaprost-containing sustained-release formulation {Sustained Release Formulation Comprising Limaprost}

The present invention relates to a sustained-release preparation containing limaprost, and more particularly, it can improve the stability of limaprost, and it can maintain the drug concentration of limaprost appropriately even with twice a day dosing regimen to show a continuous therapeutic effect. It relates to a sustained-release formulation containing limaprost that can be

Limaprost of Formula 1 ((E)-7-[(1R, 2R, 3R)-3-hydroxy-2-[(3S, 5S)-(E)-3-hydroxy-5- Methyl-1-nonenyl]-5-oxocyclopentyl]-2-heptanoic acid) is a prostaglandin E1 derivative that is used as a prophylactic or therapeutic agent for peripheral circulation disorders. etc.

[Formula 1]

Limaprost alfadex of Formula 2 below is a compound in which limaprost is clad in α-cyclodextrin.

[Formula 2]

Limaprost is mainly formulated as an oral preparation using the limaprost alphadex form. Oral formulations on the market are immediate-release formulations administered orally 3 times a day at a dose of 166.67㎍ (5㎍ as limaprost) of Limaprost Alphadex, trade names Dong-A Opalmon (Dong-A ST), Limamon Tablet (Hanmi Pharmaceutical), Opast Tablet (Youngjin Pharm) is approved.

Limaprost and limaprost alphadex are relatively unstable in the presence of a small amount of acid, base or moisture in a temperature condition of room temperature or higher, and thus there is a problem that it is difficult to handle. For this reason, research on formulations containing limaprost or limaprost alphadex has been mainly focused on improving the stability of the drug.

Republic of Korea Patent No. 10-1504862 discloses a tablet with improved stability containing a mixture of limaprost alphadex and β-cyclodextrin in an amount of 30 to 99% by weight based on 100% by weight of the total tablet. However, the tablet is an immediate-release formulation administered orally three times a day, and the blood concentration increases each time it is administered, but due to the short half-life, the blood concentration rapidly decreases over time, so that the patient is quickly stimulated by the drug and the side effect of poor sensitivity can indicate In addition, since the tablet is manufactured using a freeze-drying method, the manufacturing process is complicated and inefficient in terms of cost.

Therefore, in order to not only improve the stability of limaprost, but also to improve the patient's compliance and convenience, the sustained-release release that can show continuous therapeutic effect by maintaining the drug concentration of limaprost appropriately even with a dosing regimen twice a day The development of the formulation is required.

Republic of Korea Patent Registration No. 10-1504862

It is an object of the present invention to provide a sustained-release formulation containing limaprost that can improve the stability of limaprost as well as provide a sustained therapeutic effect by properly maintaining the drug concentration of limaprost even with twice a day dosing regimen. .

On the other hand, the present invention provides at least one selected from the group consisting of limaprost and limaprost alphadex as an active ingredient, ethyl cellulose as a sustained-release agent, hydroxypropyl betadex as a first stabilizer, and glyceryl behe as a second stabilizer Provided is a sustained-release formulation containing nate.

In the sustained-release formulation according to an embodiment of the present invention, as a sustained-release agent, at least one active ingredient selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer are dispersed in an ethyl cellulose matrix. sustained-release granules; and

and glyceryl behenate as a second stabilizer.

In one embodiment of the present invention, the sustained-release granules are prepared by dissolving at least one active ingredient selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer in a solvent, and as a sustained-release agent It may be formed by association with a mixture of ethylcellulose and hydroxypropyl betadex as a first stabilizer.

In one embodiment of the present invention, the sustained-release formulation may be formed by tableting the sustained-release granules together with glyceryl behenate as a second stabilizer.

In one embodiment of the present invention, the active ingredient may be included in an amount of 0.001 to 1% by weight based on 100% by weight of the total sustained-release formulation.

In one embodiment of the present invention, the hydroxypropyl betadex may be included in an amount of 5 to 30% by weight based on 100% by weight of the total sustained-release formulation.

In one embodiment of the present invention, the ethyl cellulose may be included in an amount of 30 to 65% by weight based on 100% by weight of the total sustained-release formulation.

In one embodiment of the present invention, the weight average molecular weight of the ethyl cellulose may be 65,000 to 215,000.

In one embodiment of the present invention, the glyceryl behenate may be included in an amount of 1 to 20% by weight based on 100% by weight of the total sustained-release formulation.

In the sustained-release formulation according to an embodiment of the present invention, when dissolution test at 50 rpm in water according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method, the active ingredient is 20-40% for 1 hour, 45-65% for 2 hours , may exhibit a release profile that elutes 60-80% for 4 hours, 80% for 8 hours or more.

On the other hand, the present invention

(i) dissolving one or more active ingredients selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer in a solvent to obtain a binding solution;

(ii) combining the binding solution with a mixture of ethyl cellulose as a sustained-release agent and hydroxypropyl betadex as a first stabilizer to obtain sustained-release granules; and

(iii) provides a method for producing a sustained-release preparation comprising the step of tableting the sustained-release granules together with glyceryl behenate as a second stabilizer.

In one embodiment of the present invention, the solvent in step (i) may be water.

The sustained-release formulation containing limaprost according to the present invention can continuously release limaprost for 8 hours or longer, so that the drug concentration of limaprost can be properly maintained even with twice a day dosing regimen to show a continuous therapeutic effect. Therefore, the sustained-release formulation according to the present invention can improve the patient's compliance with the medication and the convenience of taking it.

In addition, the limaprost-containing sustained-release formulation according to the present invention can improve the temperature and/or moisture stability of limaprost, and has the advantage that it can be manufactured more efficiently and economically.

1 is a graph showing the dissolution pattern in water of the sustained-release formulations of Examples 8 to 9 and Comparative Example 5.
Figure 2 is a graph showing the pharmacokinetic evaluation results using animals of the sustained-release formulation (test drug) containing limaprost of Example 9 and Dong-A ST Dong-A Opalmon Tablet (control drug).

Hereinafter, the present invention will be described in more detail.

One embodiment of the present invention provides at least one selected from the group consisting of limaprost and limaprost alphadex as an active ingredient, ethyl cellulose as a sustained-release agent, hydroxypropyl betadex as a first stabilizer, and glyceryl as a second stabilizer It relates to a sustained-release formulation comprising behenate.

In the sustained-release formulation according to an embodiment of the present invention, as a sustained-release agent, at least one active ingredient selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer are dispersed in an ethyl cellulose matrix. sustained-release granules; and

and glyceryl behenate as a second stabilizer.

The sustained-release preparation according to an embodiment of the present invention is prepared by dispersing an active ingredient and hydroxypropyl betadex as a first stabilizer in an ethyl cellulose matrix as a sustained-release agent to form sustained-release granules, and the sustained-release granules are prepared 2 By tableting with glyceryl behenate as a stabilizer, it is possible to not only delayed release of limaprost continuously for more than 8 hours, but also improve stability to temperature and/or moisture.

In one embodiment of the present invention, the sustained-release granule is a mixture of an active ingredient and hydroxypropyl betadex as a first stabilizer, dissolved in a solvent, ethyl cellulose as a sustained-release agent, and hydroxypropyl betadex as a first stabilizer It can be formed by association with

In one embodiment of the present invention, limaprost is a drug used as an active ingredient, for the treatment of obstructive thromboangiitis (Berger's disease) or lumbar spinal stenosis or to improve symptoms of these diseases.

The limaprost may be used in the form of a free base, a pharmaceutically acceptable salt, a racemate, an enantiomer, a polymorph, a hydrate, a solvate, a clathrate, and the like. Examples of the pharmaceutically acceptable salts include salts of inorganic acids such as hydrochloride, bromate, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and salts of organic acids such as maleate, fumarate, salicylate, succinate, citrate, acetate, lactate, tartrate, benzoate and methanesulfonate. Examples of the clathrate include limaprost alphadex. Preferably, limaprost free base or limaprost alphadex can be used.

The content of limaprost (based on free base) may be used in the range of 0.005 mg to 0.03 mg, preferably in the range of 0.005 mg to 0.015 mg. In particular, for twice a day dosing, it may be included in an amount of 0.0075 mg to 0.015 mg, for example, 0.015 mg per tablet.

In one embodiment of the present invention, the active ingredient may be included in an amount of 0.001 to 1% by weight based on 100% by weight of the total sustained-release formulation.

In one embodiment of the present invention, the hydroxypropyl betadex is included in the binding solution and the associated product together with the active ingredient as a first stabilizer to primarily stabilize the active ingredient.

The hydroxypropyl betadex may be included in an amount of 5 to 30% by weight, preferably 10 to 25% by weight, based on 100% by weight of the total sustained-release formulation. When the hydroxypropyl betadex is included in an amount of less than 5% by weight, the stability improvement effect may be insignificant, and when it is included in an amount of more than 30% by weight, it may be difficult to manufacture the granules.

The solvent may be water, such as purified water. By using water as the solvent, safety of administration can be ensured.

In one embodiment of the present invention, the ethyl cellulose serves as a sustained-release agent for delayed release of limaprost.

The weight average molecular weight of the ethyl cellulose may be 65,000 to 215,000, preferably 65,000 to 120,000. When the weight average molecular weight of the ethyl cellulose is less than 65,000, the viscosity is low and the sustained-release effect can be reduced, and when it exceeds 215,000, the viscosity is high and the sustained-release effect is excessively increased, thereby making it difficult to control the dissolution rate.

The ethyl cellulose may be included in an amount of 30 to 65% by weight, preferably 40 to 55% by weight, based on 100% by weight of the total sustained-release formulation. When the ethyl cellulose is included in an amount of less than 30% by weight, the sustained-release effect may be insignificant, and when the ethylcellulose is included in an amount of more than 65% by weight, the sustained-release effect is excessive and it may be difficult to control the dissolution rate.

In one embodiment of the present invention, the sustained-release preparation may be formed in a tablet form by tableting the sustained-release granules together with glyceryl behenate as a second stabilizer.

In one embodiment of the present invention, the glyceryl behenate serves to secondaryly stabilize the primarily stabilized active ingredient in the sustained-release granule as a secondary stabilizer.

The glyceryl behenate may be included in an amount of 1 to 20% by weight, preferably 1 to 15% by weight, based on 100% by weight of the total sustained-release formulation. When the glyceryl behenate is included in an amount of less than 1% by weight, the effect of improving stability may be insignificant, and when included in an amount of more than 20% by weight, a sustained-release effect may be exhibited, thereby affecting the dissolution rate.

The sustained-release preparation according to an embodiment of the present invention may further include a pharmaceutically acceptable additive.

Examples of the pharmaceutically acceptable additive include a diluent, a binder, a lubricant, a disintegrant, and a glidant.

The diluent serves to improve the ease of tableting and maintain the shape of the sustained-release formulation. As the diluent, mannitol, microcrystalline cellulose, betadex, lactose, glucose, etc. may be used alone or in a mixture of two or more, and in particular, mannitol, microcrystalline cellulose, or a mixture thereof may be used.

The diluent may be included in an amount of 40% by weight or less, for example, 10 to 40% by weight based on 100% by weight of the total sustained-release formulation. When the diluent is included in an amount of more than 40% by weight, the addition ratio of the sustained-release agent is relatively low, so that the sustained-release effect may be reduced.

The binder serves to increase the binding force of the sustained-release formulation. The binder includes povidone; cellulose derivatives such as hydroxypropyl cellulose and hydroxypropyl methyl cellulose; gums such as xanthan gum, alginate, and gum arabic; sugars such as starch, pregelatinized starch, and sucrose; Or a mixture thereof may be used, and in particular, povidone may be used.

The binder may be included in an amount of 1 to 10% by weight, preferably 1 to 5% by weight, based on 100% by weight of the total sustained-release formulation. When the binder is included in an amount of less than 1% by weight, it may be difficult to form granules, and when it is included in an amount of more than 10% by weight, the density of the granules may increase.

The lubricant improves the fluidity of the powder and granular material to increase the filling property to the die, which is the lower part of the tableting machine, and reduces friction between the powder and granular material and between the powder and the granular material and the punch-die, which is the upper part of the tableting machine. It serves to facilitate the compression and release of the tablet.

As the lubricant, hydrogenated castor oil, sodium stearyl fumarate, magnesium stearate, talc, etc. may be used, and in particular, hydrogenated castor oil may be used.

The lubricant may be included in an amount of 0.5 to 10% by weight based on 100% by weight of the total sustained-release formulation. When the lubricant is included in an amount of less than 0.5% by weight, tableting may be difficult, and when included in an amount of more than 10% by weight, disintegration of the formulation may be delayed to lower the dissolution rate.

In the sustained-release formulation according to an embodiment of the present invention, when dissolution test at 50 rpm in water according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test method, the active ingredient is 20-40% for 1 hour, 45-65% for 2 hours , may exhibit a release profile that elutes 60-80% for 4 hours, 80% for 8 hours or more.

The sustained-release formulation according to an embodiment of the present invention exhibits the above-described release profile, so that it can show a sustained therapeutic effect even when administered twice a day (Experimental Example 4, FIG. 1).

In addition, the sustained-release formulation according to an embodiment of the present invention has a content retention rate of 50% or more of limaprost after open storage for 2 weeks under accelerated conditions (40°C/75%RH), and acceleration in Alu-Alu packaging It is possible to reduce the generation rate of related substances in the test (40 ℃ / 75%RH), and excellent stability to temperature and / or moisture (Experimental Examples 1 to 3, Tables 5 to 8).

One embodiment of the present invention relates to a method for manufacturing a sustained-release formulation, the manufacturing method of the present invention comprises:

(i) dissolving one or more active ingredients selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer in a solvent to obtain a binding solution;

(ii) combining the binding solution with a mixture of ethyl cellulose as a sustained-release agent and hydroxypropyl betadex as a first stabilizer to obtain sustained-release granules; and

(iii) tabletting the sustained-release granules together with glyceryl behenate as a second stabilizer.

In one embodiment of the present invention, step (i) is a step of obtaining a binding solution containing an active ingredient for forming a sustained-release granule.

In step (i), a binder may be additionally used.

Detailed descriptions of the active ingredient, the first stabilizer, the solvent, and the binder are the same as those described above with respect to the sustained-release formulation.

In one embodiment of the present invention, step (ii) is a step of obtaining sustained-release granules by kneading the binding solution containing the active ingredient with a mixture of a sustained-release agent and a first stabilizer.

Step (ii) may be performed using a high speed mixer.

In one embodiment of the present invention, step (iii) is a step of tableting the sustained-release granule together with a second stabilizer, and may be performed using a conventional tableting method.

In step (iii), a pharmaceutically acceptable additive, for example, a lubricant may be additionally used together with the granulate.

As described above, in the method for producing a sustained-release preparation according to an embodiment of the present invention, a binder solution containing limaprost and the first stabilizer is combined with a mixture of the sustained-release agent and the first stabilizer to form sustained-release granules. Then, through a wet granulation and tableting process of tableting the sustained-release granules together with a second stabilizer, a sustained-release formulation with improved stability to temperature and/or moisture while allowing delayed release of limaprost is simpler and can be efficiently manufactured.

Hereinafter, the present invention will be described in more detail by way of Examples, Comparative Examples and Experimental Examples. These Examples, Comparative Examples, and Experimental Examples are only for illustrating the present invention, and it is apparent to those skilled in the art that the scope of the present invention is not limited thereto.

Example 1 and Comparative Examples 1 to 3: Preparation of limaprost sustained-release formulation according to the type of cyclodextrin

Limaprost sustained-release formulation was prepared according to the following method with the composition of Table 1 below (unit: wt%).

Limaprost alphadex clathrate compound is dissolved in purified water with povidone as a binder and betadex, hydroxypropyl betadex or gammadex as a first stabilizer to prepare a binding solution, and then the binding solution is mixed with a high speed mixer ) and kneaded into a mixture of a diluent, a first stabilizer, and a sustained-release agent to obtain a wet granulate. The obtained wet granules were dried at 50° C. using a fluidized bed dryer, and then tableted by adding a second stabilizer and a lubricant.

Manufacture process ingredient Kinds Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 binder Limaprost Alphadex Inclusion Compound chief ingredient 0.34 0.34 0.34 0.34 povidone binder 2.00 2.00 2.00 2.00 Betadex first stabilizer - 7.50 - - hydroxypropyl betadex first stabilizer 7.50 - - - Gammadex first stabilizer - - 7.50 - Union mannitol diluent 13.28 13.28 13.28 20.38 Microcrystalline Cellulose diluent 13.28 13.28 13.28 20.39 Betadex first stabilizer 6.71 hydroxypropyl betadex first stabilizer 6.71 Gammadex first stabilizer 6.71 Ethyl Cellulose (Mw: 65,000) sustained release agent 42.59 42.59 42.59 42.59 post-mix glyceryl behenate second stabilizer 13.30 13.30 13.30 13.30 hydrogenated castor oil lubricant 1.00 1.00 1.00 1.00 total 100.00 100.00 100.00 100.00

Examples 2 to 4: Preparation of limaprost sustained-release formulation according to the hydroxypropyl betadex content

Limaprost sustained-release formulation was prepared by varying the hydroxypropyl betadex content according to the same method as in Example 1 with the composition shown in Table 2 below (unit: wt%).

Manufacture process ingredient Kinds Example 2 Example 3 Example 4 binder Limaprost Alphadex Inclusion Compound chief ingredient 0.34 0.34 0.34 hydroxypropyl betadex first stabilizer 6.45 9.68 13.42 povidone binder 2.68 2.68 2.68 Union mannitol diluent 13.42 11.80 10.74 Microcrystalline Cellulose diluent 13.42 11.80 10.74 hydroxypropyl betadex first stabilizer 6.71 6.71 6.71 Ethyl Cellulose (Mw: 65,000) sustained release agent 49.03 49.04 47.42 post-mix glyceryl behenate second stabilizer 7.15 7.15 7.15 hydrogenated castor oil lubricant 0.80 0.80 0.80 total 100.00 100.00 100.00

Examples 5 to 7 and Comparative Example 4: Preparation of limaprost sustained-release formulation according to the glyceryl behenate content

Limaprost sustained-release formulation was prepared by varying the glyceryl behenate content according to the same method as in Example 1 with the composition shown in Table 3 below (unit: wt%).

Manufacture process ingredient Kinds Example 5 Example 6 Example 7 Comparative Example 4 binder Limaprost Alphadex
clathrate chief ingredient 0.34 0.34 0.34 0.34 hydroxypropyl betadex first stabilizer 13.42 13.42 13.42 13.42 povidone binder 2.68 2.68 2.68 2.68 Union mannitol diluent 16.05 15.28 14.50 16.05 Microcrystalline Cellulose diluent 16.05 15.28 14.50 16.05 hydroxypropyl betadex first stabilizer 6.71 6.71 6.71 6.71 Ethyl Cellulose (Mw: 65,000) sustained release agent 41.69 39.60 38.88 42.74 post-mix glyceryl behenate second stabilizer 1.05 4.78 7.15 - hydrogenated castor oil lubricant 2.01 1.91 1.82 2.01 total 100.00 100.00 100.00 100.00

Examples 8 to 9 and Comparative Example 5: Preparation of limaprost sustained-release formulation according to the ethyl cellulose content

Limaprost sustained-release formulation was prepared by varying the ethyl cellulose content according to the same method as in Example 1 with the composition shown in Table 4 below (unit: wt%).

Manufacture process ingredient Kinds Example 8 Example 9 Comparative Example 5 binder Limaprost Alphadex Inclusion Compound chief ingredient 0.34 0.34 0.34 hydroxypropyl betadex first stabilizer 13.42 13.42 13.42 povidone binder 2.68 2.68 2.68 Union mannitol diluent 4.54 10.74 31.28 Microcrystalline Cellulose diluent 4.54 10.74 31.28 hydroxypropyl betadex first stabilizer 6.71 6.71 6.71 Ethyl Cellulose (Mw: 65,000) sustained release agent 53.47 41.07 - post-mix glyceryl behenate second stabilizer 7.15 7.15 7.15 hydrogenated castor oil lubricant 7.15 7.15 7.15 total 100.00 100.00 100.00

Experimental Example 1: Stability test according to the type of cyclodextrin

For the stability test according to the type of cyclodextrin as the first stabilizer, the sustained-release formulations of Examples 1 and Comparative Examples 1 to 3 were opened and stored under accelerated conditions (40° C./75% RH), respectively, and the content retention rate of limaprost was analyzed.

Limaprost content analysis was measured by high-performance liquid chromatography (HPLC). For HPLC, Agilent 1200 series, column C18 (5㎛, 4.6×150mm) was used, and the mobile phase was prepared with 0.02M potassium dihydrogen phosphate buffer/acetonitrile/isopropanol (50/25/10) and UV detector at 215nm. was detected using

The results are shown in Table 5 below.

Open / Accelerated conditions (40℃/75%RH) Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Early 99.01% 98.30% 98.83% 97.92% 1 week 74.28% 63.26% 28.38% 29.23% 2 weeks 59.42% 37.55% 3.92% - 3 weeks 44.99% 23.56% 2.74% -

Through Table 5, Example 1 to which hydroxypropylbetadex was added showed a remarkably good stabilizing effect, and Comparative Examples 1 and 2 to which betadex or gammadex was added, and Comparative Example 2 to which no stabilizer was added. It can be seen that Example 3 has poor stability.

Experimental Example 2: Stability test according to hydroxypropyl betadex content

For the stability test according to the hydroxypropylbetadex content as the first stabilizer, the sustained-release formulations of Examples 2 to 4 and two commercially available formulations were stored open under accelerated conditions (40°C/75%RH) and then Lima Frost content retention rate was analyzed. Limaprost content analysis was performed in the same manner as described in Experimental Example 1.

The results are shown in Table 6 below.

Open / Accelerated conditions (40℃/75%RH) Example 2 Example 3 Example 4 Commercial preparation 1 Commercial preparation 2 Early 105.42% 103.85% 107.57% 103.11% 100.9% 1 week 75.48% 83.91% 97.94% 71.23% 71.67% 2 weeks 55.25% 68.84% 93.27% 54.63% 54.87%

From Table 6, it can be seen that as the hydroxypropyl betadex content is increased, the stability of the tablet to heat and moisture is improved.

In addition, an accelerated test (40 ° C / 75% RH) in Example 4 and Alu-Alu packaging of Commercial Formulation 1, which showed the most improved results of stability, was performed, and 11-deox of the following formula (a), which is a major related substance of limaprost, The rate of change of the body was measured using UPLC.

[Formula a]

The results are shown in Table 7 below.

Alu-Alu packaging, 40℃/75%RH Example 4 Commercial preparation 1 11-deoxy (%) 11-deoxy (%) Early 0.49 1.42 1 month 0.75 1.45 3 months 1.27 1.81 6 months 1.69 1.90

Through Table 7, it was confirmed that Example 4 had a lower rate of change of related material 11-deoxy than that of Commercial Formulation 1, and thus had better stability.

Experimental Example 3: Stability test according to the content of glyceryl behenate

For the stability test according to the content of glyceryl behenate as a second stabilizer, the sustained-release formulations of Examples 5 to 7 and Comparative Example 4 were stored open under accelerated conditions (40° C./75% RH) and then the content of limaprost The retention rate was analyzed. Limaprost content analysis was performed in the same manner as described in Experimental Example 1.

The results are shown in Table 8 below.

Open / Accelerated conditions (40℃/75%RH) Example 5 Example 6 Example 7 Comparative Example 4 Early 98.50% 99.76% 98.66% 99.42% 1 week 75.62% 82.52% 88.55% 35.16% 2 weeks 60.79% 70.99% 83.49% 1.02%

From Table 8, it can be seen that as the content of glyceryl behenate increases, the stability of the tablet against heat and moisture is improved.

Experimental Example 4: Dissolution rate test according to ethyl cellulose content

In order to find out the change in dissolution rate according to the content of ethyl cellulose as a sustained-release agent, a dissolution test in water of the sustained-release formulations of Examples 8 to 9 and Comparative Example 5 was performed.

The dissolution test was performed according to the second method (paddle method) of the Korean Pharmacopoeia dissolution test, and the dissolution was carried out under the conditions of 900 ml of dissolution (water), a paddle rotation speed of 50 rpm, and a temperature of 37 ± 0.5°C. After 1 hour, 2 hours, 4 hours, and 8 hours after the test elapsed, it was filtered through a 0.45 μm filter and analyzed using high-performance liquid chromatography (HPLC).

The results are shown in FIG. 1 .

1, it can be seen that as the content of ethyl cellulose as the sustained-release agent increases, the increase in the dissolution rate over time decreases, and when ethyl cellulose is not included as the sustained-release agent, sustained-release properties do not appear.

Experimental Example 5: Pharmacokinetic evaluation using beagle dogs

Using Example 9 as a test drug and Dong-A ST Dong-A Opalmon Tablet (Limaprost alpha-cyclodextrin inclusion compound) as a reference drug, a pharmacokinetic test in Beagle dogs was performed as follows.

A total of 12 healthy beagle dogs were divided into 2 groups of 6 each, and a cross-experiment was conducted by oral drug administration. For accurate evaluation, animals were tested after fasting for 12 hours before drug administration. Six tablets of each of the test drug and the reference drug were orally administered together with 20-30 mL of water. After administration, venous blood was collected for a set time interval, and plasma was collected by centrifugation immediately after blood collection and stored frozen. The analysis of limaprost in plasma was quantitatively analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). The peak plasma concentration (Cmax) and the time to reach the peak plasma concentration (Tmax) were obtained from the blood concentrations calculated according to the results of quantitative analysis, and a graph (AUCt) showing the relationship between the blood concentration and time of the administered drug was obtained. Pharmacokinetic evaluation was finally evaluated based on the pharmacokinetic parameters (Cmax, Tmax, AUCt) calculated from the commercial preparation (control drug) and sustained-release preparation (test drug).

The results are shown in FIG. 2 .

2, the maximum blood concentration (Cmax) of the reference drug and the test drug was 9.89 pg/mL and 13.26 pg/mL, respectively, and the time to reach the maximum blood concentration (Tmax) was 0.6 hr and 0.74 hr, respectively, and the reference drug And it can be seen that the AUCt of the test drug is 15.38 hr.pg/mL and 29.02 hr.pg/mL, respectively.

As a result of pharmacokinetic evaluation, the ratio of AUCt of the test drug and the reference drug when converted into administration 3 times a day and twice a day administration of the reference drug and the test drug is about 1.26, and the ratio of Cmax is 1.34, which is almost similar. , and in the case of Tmax, it was confirmed that the test drug increased by 0.14 hr compared to the control drug. Through this, it can be seen that the drug release is delayed in the formulation according to the present invention, and it was confirmed that the drug was detected up to 8 hours and exhibited sustained release properties.

As the specific part of the present invention has been described in detail above, for those of ordinary skill in the art to which the present invention pertains, it is clear that these specific techniques are only preferred embodiments, and the scope of the present invention is not limited thereto. Do. Those of ordinary skill in the art to which the present invention pertains will be able to make various applications and modifications within the scope of the present invention based on the above contents.

Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (12)

At least one selected from the group consisting of limaprost and limaprost alphadex as an active ingredient, ethyl cellulose as a sustained-release agent, hydroxypropyl betadex as a first stabilizer, and glyceryl behenate as a second stabilizer. formulation. The sustained-release granule of claim 1, wherein at least one active ingredient selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer are dispersed in an ethyl cellulose matrix as a sustained-release agent; and
A sustained-release formulation comprising glyceryl behenate as a second stabilizer. According to claim 2, wherein the sustained-release granules are dissolved in one or more active ingredients selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer in a solvent, and ethyl cellulose as a sustained-release agent And a sustained-release formulation formed by associating with a mixture of hydroxypropyl betadex as a first stabilizer. The sustained-release formulation of claim 2, wherein the sustained-release formulation is formed by tableting the sustained-release granules together with glyceryl behenate as a second stabilizer. The sustained-release preparation according to claim 1, wherein the active ingredient is included in an amount of 0.001 to 1% by weight based on 100% by weight of the total sustained-release preparation. The sustained-release formulation of claim 1, wherein the hydroxypropyl betadex is included in an amount of 5 to 30% by weight based on 100% by weight of the total sustained-release formulation. The sustained-release formulation according to claim 1, wherein the ethyl cellulose is included in an amount of 30 to 65% by weight based on 100% by weight of the total sustained-release formulation. The sustained-release formulation according to claim 1, wherein the weight average molecular weight of the ethyl cellulose is 65,000 to 215,000. The sustained-release formulation of claim 1, wherein the glyceryl behenate is included in an amount of 1 to 20% by weight based on 100% by weight of the total sustained-release formulation. According to claim 1, when dissolution test in water at 50 rpm according to the dissolution test method 2 (paddle method) of the Korean Pharmacopoeia, the active ingredient is 20-40% for 1 hour, 45-65% for 2 hours, 60-80 for 4 hours %, a sustained-release formulation that exhibits a release profile that dissolves at least 80% over 8 hours. (i) dissolving one or more active ingredients selected from the group consisting of limaprost and limaprost alphadex and hydroxypropyl betadex as a first stabilizer in a solvent to obtain a binding solution;
(ii) combining the binding solution with a mixture of ethyl cellulose as a sustained-release agent and hydroxypropyl betadex as a first stabilizer to obtain sustained-release granules; and
(iii) a method for producing a sustained-release preparation comprising the step of tableting the sustained-release granules together with glyceryl behenate as a second stabilizer. The method according to claim 11, wherein the solvent in step (i) is water.

Images